Vindesine is disclosed in the copending application of Cullinan, and Gerzon, Ser. No. 828,693 filed Aug. 29, 1977, and is named therein as 4-desacetyl VLB C-3 carboxamide. The compound has the following structure ##STR1## Vindesine can also be named as 4-desacetyl-3-descarbomethoxy VLB 3-carboxamide or as 23-amino-O.sup.4 -desacetyl-23-demethoxy-vincaleukoblastine. A sulfate salt of vindesine is also specifically disclosed in Ser. No. 828,693. This sulfate is obtained by neutralization of vindesine base with dilute sulfuric acid followed by lyophilization. The salt thus obtained is electrostatic, hygroscopic and unstable upon storage.
It has now been found that there are three salts of vindesine formed with sulfuric acid. These salts are the hemisulfate, monosulfate and disulfate salts. The dissociation constant of sulfuric acid is such that, unless a strong base is present, the sole ionization of importance is EQU H.sub.2 SO.sub.4 .revreaction.H.sup.+ +HSO.sub.4.sup.-
Vindesine has three basic groups, those at N-9, N-6 and N-1, but titration of vindesine shows only two titratable basic groups, probably at N-9 and N-6. In the monosulfate salt, probably one mole of bisulfate (HSO.sub.4.sup.-) and one mole of vindesine react, the salt forming on the most basic amine group. The hemisulfate is formed from one mole of sulfuric acid and two moles of vindesine. In the disulfate, two of the basic amine groups in vindesine react with bisulfate ions, giving a 1:2 ratio of base to acid.
In transplanted tumor systems in animals, vindesine has shown an activity approaching that of vincristine although potentially lacking some of the neurological side-effects which accompany the clinical use of the latter drug. Vindesine is now undergoing a world-wide clinical trial and so far appears in early tests to be active against certain leukemias and lymphomas, and against both small cell and non-small cell carcinomas, particularly in conjunction with cis-platinum.
Vinblastine and vincristine, two vinca alkaloids related to vindesine, now being marketed as oncolytic agents, are formulated as sulfate salts for use in intravenous administration to patients suffering from various neoplasms. The formulations are freeze dried and reconstituted by adding water just prior to use. In such a formulation, the drug should go into solution rapidly and completely. As previously stated, titration of vindesine base with dilute sulfuric acid and then evaporating the resulting solution to dryness yielded a salt which was electrostatic and hygroscopic (difficult to handle) and its stability was unsatisfactory on storage.
It is an object of this invention to provide a method for the preparation of a vindesine salt which yields a product of good shelf stability, which is easy to handle, and which reconstitutes rapidly in water to form a solution.